The present invention relates to novel 6-substituted acyclopyrimidine derivatives and antiviral agents containing the derivative as the active ingredients.
Infectious diseases caused by human acquired immunodeficiency virus (HIV), which is a type of retrovirus, have recently become a serious social problem. A compound of 3xe2x80x2-deoxy-3xe2x80x2-azidothymidine is known as a nucleoside compound used in the clinical treatment for diseases caused by HIV-infection. However, this compound has side-effects since it also exhibits considerable strong toxicity in the host cells.
Although some 2xe2x80x2,3xe2x80x2-dideoxyribonucleosides are known as nucleoside compounds exhibiting an anti-viral activity, it is still necessary to develop a substance possessing a higher activity and lower toxicity to the host cell (Hiroaki Mitsuya, Bodily Defense, Vol. 4, pp.213-223 (1987)).
On the other hand, various acyclonucleoside compounds have been synthesized since Acyclovir (acycloguanosine) was developed as an antiviral substance effective against herpes virus (C. K. Chu and S. J. Culter, J. Heterocyclic Chem., 23, p.289 (1986)). However, no acyclonucleoside compound having a sufficient activity especially against retroviruses has yet been discovered.
We have focussed our attention on 6-substituted acyclopyrimidine nucleoside compounds and have synthesized various novel 6-substituted acyclopyrimidine nucleoside derivatives and screened those compounds to detect effective antiviral agents, especially to the retrovirus, in order to provide antiviral agents exhibiting an effective activity particularly against retroviruses.
Some 6-substituted acyclopyrimidine nucleoside compounds such as 6-fluoro substituted derivatives, 6-alkylamino substituted derivatives (DD-A-232492) and 6-methyl substituted derivatives (C. A. 107, 129717w (1987)) are known; however, the antiviral activity of these compounds has not been described.
As a result of our researches for compounds exhibiting an effective antiviral activity, particularly anti-retroviral activity, we found that specific 6-substituted pyrimidine nucleoside compounds according to the invention satisfy the above demand to achieve the present invention.
The present invention concerns 6-substituted acyclopyrimidine nucleoside derivatives represented by the following general formula I; 
wherein R1 represents a hydrogen atom, halogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, arylcarbonylalkyl, arylthio or aralkyl group;
R2 represents an arylthio, alkylthio, cycloalkylthio, arylsulfinyl, alkylsulfinyl, cycloalkylsulfinyl, alkenyl, alkynyl, aralkyl, arylcarbonyl, arylcarbonylalkyl or aryloxy group, those groups optionally substituted by one or more of substituents selected from a halogen atom, alkyl, halogenated alkyl, alkoxy, hydroxyl, nitro, amino, cyano and acyl groups;
R3 represents a hydrogen atom, methyl, branched alkyl or xe2x80x94CH2xe2x80x94Zxe2x80x94(CH2)nxe2x80x94R5 group where R5 represents a hydrogen atom, halogen atom, hydroxyl, heterocyclic carbonyloxy, formyloxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, aralkylcarbonyloxy, arylcarbonyloxy, azido, alkoxycarbonyloxy, N-alkylcarbamoyloxy, N-arylcarbamoyloxy, alkoxy, aralkyloxy, branched alkyl, cycloalkyl or aryl group, the alkoxycarbonyloxy to aryl groups mentioned above as R5 optionally substituted by one or more substituents selected from a halogen atom, aryl, alkyl, alkoxy and halogenated alkyl groups, Z represents an oxygen, sulfur atom or methylene group, and n represents 0 or an integer of 1 to 5,
R4 represents a hydrogen atom, alkyl or aralkyl group,
X and Y represent an oxygen or sulfur atom independently, provided that when R4 and Z represent a hydrogen atom and oxygen atom respectively R5 does not represent a hydroxyl group, or the following general formula Ixe2x80x2; 
wherein R1, R2, R3 and Y have the same meanings as defined for the formula I above, pharmaceutically acceptable salts thereof and antiviral agents containing the derivative or the salt thereof as an active ingredient.
The 6-substituted acyclopyrimidine nucleoside derivatives according to the invention are represented by the general formula I or Ixe2x80x2.
The group of R1 represents a hydrogen atom; halogen atom such as chlorine, iodine, bromine and fluorine; alkyl group such as methyl, ethyl, n-propyl, i-propyl and n-butyl; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; alkenyl group such as vinyl, propenyl, butenyl, phenylvinyl, bromovinyl, cyanovinyl, alkoxycarbonylvinyl and carbamoylvinyl; alkynyl group such as ethynyl, propynyl and phenylethynyl; alkylcarbonyl group such as acetyl, propionyl, and i-butyryl; arylcarbonyl group such as benzoyl and naphthoyl; arylcarbonylalkyl group such as phenacyl; arylthio group such as phenylthio, tolylthio and naphthylthio; or aralkyl group such as benzyl.
The group of R2 represents an arylthio group such as phenylthio and naphthylthio; alkylthio group such as methylthio, ethylthio, propylthio, butylthio and pentylthio; cycloalkylthio group such as cyclopentylthio, cyclohexylthio and cycloheptylthio; arylsulfinyl group such as phenylsulfinyl; alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl and butylsulfinyl; cycloalkylsulfinyl group such as cyclopentylsulfinyl and cyclohexylsulfinyl; alkenyl group such as vinyl, propenyl and phenylvinyl; alkynyl group such as ethynyl, propynyl and phenylethynyl; aralkyl group such as benzyl; arylcarbonyl group such as benzoyl; arylcarbonylalkyl group such as phenacyl; or aryloxy group such as phenoxy, and those groups may be optionally substituted by one or more of substituents selected from a halogen atom such as chlorine, bromine, fluorine and iodine, alkyl group such as methyl, ethyl, propyl, butyl and pentyl, a halogenated alkyl group such as trifluoromethyl, alkoxy group such as methoxy, ethoxy, propoxy and butoxy, hydroxyl group, nitro group, amino group, cyano group and acyl group such as acetyl.
The group of R3 represents a hydrogen atom, methyl group, branched alkyl group such as i-propyl and t-butyl or xe2x80x94CH2xe2x80x94Zxe2x80x94(CH2)nxe2x80x94R5 group where R5 represents a hydrogen atom; halogen atom such as fluorine, chlorine, iodine and bromine; hydroxyl group; heterocyclic carbonyloxy group such as nicotinoyloxy; formyloxy group; optionally branched alkylcarbonyloxy group such as acetoxy, propyonyloxy, n-butyryloxy, i-butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy and decanoyloxy; cycloalkylcarbonyloxy group such as cyclohexylcarbonyloxy; aralkylcarbonyloxy group such as benzylcarbonyloxy; arylcarbonyloxy group such as benzoyloxy, toluoylcarbonyloxy and naphthoylcarbonyloxy group; azido group; alkoxycarbonyloxy group such as methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, i-propoxycarbonyloxy, n-butoxycarbonyloxy and t-butoxycarbonyloxy group, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; N-alkylcarbamoyloxy group such as N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-propylcarbamoyloxy, N-butylcarbamoyloxy and N-pentylcarbamoyloxy, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; N-arylcarbamoyloxy group such as N-phenylcarbamoyloxy and N-tolylcarbamoyloxy, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; N-alkylthiocarbamoyloxy group such as N-methytiocarbamoyloxy, N-ethylthiocarbamoyloxy, N-propylthiocarbamoyloxy, N-butylthiocarbamoyloxy and N-pentylthiocarbamoyloxy, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; N-arylthiocarbamoyloxy group such as N-phenylthiocarbamoyloxy and N-tolylthiocarbamoyloxy, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentyloxy and n-hexyloxy group, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; branched alkyl group such as i-propyl, i-butyl, sec-butyl, t-butyl, i-heptyl and i-hexyl, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; or aryl group such as phenyl, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, an alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl, and Z represents an oxygen, sulfur atom or methylene group, and n represents 0 or an integer of 1 to 5,
R4 represents a hydrogen atom; optionally branched alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl; or aralkyl group such as benzyl.
X and Y represent oxygen or sulfur atom independently.
In the above formula I, when R4 and Z represent a hydrogen atom and oxygen atom respectively, R5 does not represent a hydroxyl group.
The preferred compounds according to the invention have R1 of a hydrogen atom, halogen atom, C1 to C5 alkyl group or C2 to C5 alkenyl group, particularly C1 to C5 alkyl group; R2 of C6 to C10 arylthio group, C3 to C10 cycloalkylthio group or C7 to C11 aralkyl group, particularly C6 to C10 arylthio, C3 to C10 cycloalkylthio or C7 to C11 aralkyl group, optionally substituted by one or more substituents selected from a halogen atom, C1 to C5 alkyl, C1 to C5 alkoxy and nitro groups; R3 of a hydrogen atom, methyl or xe2x80x94CH2xe2x80x94Zxe2x80x94(CH2)nxe2x80x94R5 group where R5 represents a hydrogen atom, halogen atom, hydroxyl, heterocyclic carbonyloxy, C2 to C11 alkylcarbonyloxy, C4 to C10 cycloalkylcarbonyloxy, C8 to C12 aralkylcarbonyloxy, C7 to C13 arylcarbonyloxy, C2 to C11 alkoxycarbonyloxy, C8 to C10 aralkyloxycarbonyloxy, C2 to C8 N-alkylcarbamoyloxy, C7 to C13 arylcarbamoyloxy, C2 to C8 alkylthiocarbamoyloxy, C7 to C13 arylthiocarbamoyloxy, C1 to C10 alkoxy, C7 to C13 aralkyloxy, azido, C3 to C5 branched alkyl, C5 to C7 cycloalkyl or C6 to C10 aryl group optionally substituted by one or more substituents selected from a halogen atom, aryl, alkyl, alkoxy and halogenated alkyl groups, Z represents an oxygen, sulfur atom or methylene group, and n represents 0 or an integer of 1 to 5; R4 of a hydrogen atom, C1 to C13 alkyl or C7 to C11 aralkyl group; X of an oxygen or sulfur atom; and Y of an oxygen or sulfur atom; provided that when R4 and Z represent a hydrogen atom and oxygen atom respectively R5 does not represent hydroxyl group,
Examples of the preferred compounds according to the present invention are listed in Table 1 below. t,120
The compounds according to the invention of the formula I wherein R3 represents methyl or branched alkyl or xe2x80x94CH2xe2x80x94Z(CH2)nxe2x80x94R5 group where R5 represents a hydrogen, halogen atom, azido, alkoxy, aralkyloxy, optionally substituted aryl group or the like may be prepared in accordance with the following reaction formula (1), (2) or (3): 
wherein R1, R2, R3, R4, X and Y have the same meanings defined hereinbefore, X1 and X2 represent a halogen atom, arylthio, alkoxy group or the like, and M represents an alkaline metal.
Firstly, the compound of the formula II or IV is treated with an organic alkali metal compound in an ether solvent such as diethyl ether and tetrahydrofuran at a temperature of xe2x88x9280xc2x0 to xe2x88x9210xc2x0 C. for 0.2 to 10 hours.
Examples of the organic alkali metal compound include potassium bistrimethylsilylamide, sodium bistrimethylsilylamide and lithium alkylamide, and particularly preferred compounds among those are lithium diisopropylamide (LDA) and lithium 2,2,6,6-tetramethylpiperidide (LTMP). Such lithium alkylamides are preferably prepared immediately before the reaction. For example, lithium dialkylamide may be prepared by reacting a secondary amine such as diisopropylamine with an alkyl lithium such as n-butyl lithium in a solvent such as diethyl ether, dioxane, tetrahydrofuran and dimethoxyethane with stirring under the atmosphere of an inert gas such as argon at xe2x88x9280xc2x0 C. to xe2x88x9210xc2x0 C. for 0.2 to 5 hours.
The organic alkali metal compound is usually used in an amount of 1 to 5 moles per mole of the compound of the general formula II or IV.
Then, the electrophilic reagent of the general formula R2X1 or R1X2 is added to the reaction mixture in a ratio of about 1 to 5 moles to the compound of the general formula II or IV to allow the reaction under the same condition as in the reaction with the organic alkali metal compound.
The electrophilic reagent should have a group of R1 or R2 defined above, and examples of this reagent includes various diaryl disulfides, arylsulfenyl chlorides, dialkyl disulfides, dicycloalkyl disulfides, alkyl halides, aralkyl halides such as benzyl bromide, acid halides such as benzoyl halide and isobutyric halide, acid anhydrides and esters thereof, aryl-carbonylalkyl halides such as phenacyl chloride and the like.
The compounds of the general formula II can be prepared by a conventional method.
The compounds of the general formula IV can be prepared in accordance with the reaction formula (I) above (R1xe2x95x90H). 
wherein R1, R2, R3, R4, X and Y have the same meanings defined hereinbefore and X3 represents a halogen atom such as chlorine, bromine and iodine or sulfonyloxy group such as toluenesulfonyloxy and mesyloxy groups.
The compounds of the general formula VI are treated with an acid such as hydrochloric acid and bromic acid in a suitable solvent, for example, an alcohol such as methanol and ethanol and water at an appropriate temperature of from room temperature to 100xc2x0 C. to obtain the compounds of the general formula VII.
Then, the compounds of the general formula VII are reacted with the compounds of the general formula VIII in a suitable solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile and tetrahydrofuran in the presence of a suitable base such as sodium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate and sodium carbonate at a temperature of from ambient temperature to the boiling point of the solvent to obtain the compounds of the general formula I.
The starting compounds represented by the general formula VI can be prepared in accordance with the reaction formula (1) or (2).
When the objective compound has a hydroxyl group of R5 or when any intermediate compound of the reactions has a hydroxyl group, the reactions of (1) and (2) should be carried out using a starting compound or intermediate compound of which hydroxyl group is protected by an appropriate protective group instead of the unprotected compound of the formula II or IV or the like, and the protective group is then eliminated to obtain the target compound.
Any protective groups conventionally used for the protection of hydroxyl group may be used for this purpose so long as it is not eliminated under the alkaline condition.
Examples of such protective group are aralkyl groups such as benzyl, trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, tetrahydropyranyl group and substituted alkyl groups such as methoxymethyl group. Among those protective groups, silyl groups are particularly preferred.
The introduction of the protective group can be carried out by a conventional method.
For example, the introduction of the protective silyl group may be carried out by reacting the compound having the hydroxyl group with 1 to 10 times by mole of silylating reagent such as trimethylsilyl chloride and t-butyldimethylsilyl chloride at a temperature of from 0xc2x0 to 50xc2x0 C. in the presence of a base such as pyridine, picoline, diethylaniline, dimethylaniline, triethylamine and imidazole in a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran and a mixture of those solvents in any combination.
The elimination of the protective group may be carried out by a conventional method corresponding to the kind of the protective group, for example, acid hydrolysis, ammonium fluoride treatment or catalytic reduction.
The compounds obtained by the reactions (1), (2) or (3) which have a nitro substituted phenylthio group at the 6-position may be converted into the compounds having an amino group by hydrogenation in accordance with the reaction formula (4) below. The hydrogenation can be carried out in an organic solvent such as alcohol and acetic acid in the presence of a catalyst such as palladium/carbon at an appropriate temperature of from room temperature to 80xc2x0 C.: 
wherein the symbols have the same meanings as defined above.
The compounds having an arylthio, alkylthio or cycloalkylthio group can be converted to corresponding compounds having an arylsulfinyl, alkylsulfinyl or cycloalkylsulfinyl group by using an oxidizing agent such as hydrogen peroxide and m-chloroperbenzoic acid in accordance with the reaction formula (5) below: 
wherein R6 represents an aryl, alkyl or cycloalkyl group and the other symbols have the same meanings as defined above.
The compounds having phenyl sulfoxide group can be converted into corresponding compounds having a substituted arylthio or aryloxy group by reacting with sodium arylthiolate or sodium aryloxide having various substituents on the benzene ring in an organic solvent such as tetrahydrofuran, alcohol, dimethylformamide and acetonitrile at an appropriate temperature of from room temperature to 100xc2x0 C. in accordance with the reaction formula (6) below: 
wherein A represents a sulfur or oxygen atom, R7 and R8 independently represent a halogen atom such as chlorine, bromine, fluorine and iodine, alkyl group such as methyl, ethyl, propyl and butyl, halogenated alkyl group such as trichloromethyl, alkoxy group such as methoxy, ethoxy, propoxy and butoxy, hydroxyl group, nitro group, amino group, cyano group and acyl group such as acetyl, and the other symbols have the same meanings as defined above.
The present compounds may be also prepared in accordance with, for example, the reaction formula (7) or (8) below: 
wherein R9 represents an alkyl group such as methyl and ethyl, aryl group such as phenyl and toluyl, a protective group such as silyl group or the like, and the other symbols have the same meanings as defined above.
The reactions of the formulae (7) and (8) can be carried out in an amine solvent such as diethylamine and triethylamine in the presence of a palladium catalyst at an appropriate temperature of from room temperature to 70xc2x0 C. The reactions may be carried but more homogeneously by adding another solvent such as acetonitrile. As the catalyst, a palladium catalyst of bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium(O) and bis(diphenylphosphino)ethanepalladium dichloride can be used in combination with cuprous iodide.
The present compounds can be prepared also in accordance with the reaction formula (9) or (10) below, and the reactions may be carried out in the same manner as the reactions of the formulae (7) and (8) except that an olefin derivative of H2Cxe2x95x90CHxe2x80x94R10 wherein R10 represents an alkoxycarbonyl, nitrile, carbamoyl group and the like is used instead of the acetylene derivative in the reactions of the formulae (7) and (8): 
wherein the symbols have the same meanings as defined above.
The palladium catalyst may be the same as in the reaction of the formulae (7) and (8).
The compounds according to the invention can be prepared also in accordance with the reaction formula (11) below: 
wherein X4 represents a halogen atom such as chlorine, bromine and iodine, and the other symbols have the same meaning as defined above.
The compounds according to the invention can be prepared also in accordance with the reaction formula (12) or (13) below: 
wherein the symbols have the same meanings as defined hereinbefore.
In the reactions of the formulae (12) and (13), intermediate compounds are prepared in accordance with the reaction formulae (1) and (2) as described hereinbefore except that a compound of OCH-CH(R11)(R12) wherein R11 and R12 independently represent a hydrogen atom, alkyl group such as methyl, ethyl and propyl or aryl group such as phenyl is used instead of the compounds R1X2 and R2X1, and then the intermediate compounds are dehydrated by a dehydrating agent such as mesyl chloride, tosyl chloride and thionyl chloride to produce the compounds according to the invention having an alkenyl group.
By hydrogenation, the alkynyl group of the compounds produced in the reactions of the formula (7) or (8) can be converted into the corresponding alkenyl or alkyl group and the alkenyl group of the compound produced in any one of the reactions formulae (9) to (13) can be converted into the corresponding alkyl group. For the reduction of alkynyl group into alkenyl group, the hydrogenation may be carried out at an appropriate temperature of from room temperature to 80xc2x0 C. under hydrogen atmosphere in the presence of a catalyst such as palladium/barium sulfate, palladium/calcium carbonate, palladium/calcium carbonate/lead acetate and palladium/barium sulfate/quinoline in a solvent such as alcohol and acetic acid. For the reduction of alkenyl or alkynyl group into alkyl group, the hydrogenation may be carried out by using a catalyst such as palladium/carbon and palladium hydroxide under the same conditions as used for producing the alkenyl group.
The 6-benzyl substituted derivatives of the invention may be prepared in accordance with the reaction formula (14) below: 
wherein the symbols have the same meanings as defined hereinbefore
In the reactions of the formula (14), intermediate compounds are prepared in the same way as the reactions of the formula (1) using OHC-R13 where R13 represents an optionally substituted aryl group such as phenyl instead of R1X2 and the intermediate compounds are reduced by a suitable reducing agent to convert the hydroxyl group into a hydrogen atom. The reduction can be carried out by using hydrogen gas in the presence of palladium/carbon or palladium hydroxide.
The 6-substituted acyclouridine or acyclothymidine derivatives obtained in the above-described reactions can be converted into 4-thio derivatives by heating them with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in a solvent such as toluene and xylene in accordance with the reaction formula (15) below: 
wherein the symbols have the same meanings as defined hereinbefore.
The 4-thio derivatives can be also prepared by preparing corresponding 4-chloro derivatives by chlorination of corresponding uridine or thymidine derivatives by a chlorinating agent such as phosphorous pentachloride or phosphorous oxychloride and reacting the 4-chloro derivatives with sodium bisulfide.
Further, 4-amino derivatives can be prepared by reacting the acyclouridine or thymidine derivatives with 1-(2-mesitylenesulfonyl)-3-nitro-1,2,4-triazole in the presence of diphenylphosphoric acid in a solvent such as pyridine to produce corresponding 4-(3-vitro-1,2,4-triazole) derivatives which are converted to the corresponding 4-amino derivatives by aqueous ammonia at an appropriate temperature of from room temperature to 100xc2x0 C. in accordance with the reaction formula (16) below: 
wherein the symbols have the same meanings as define hereinbefore.
Thus, the compounds of the invention represented by the formula Ixe2x80x2 are prepared as described above.
The above-obtained compounds where R4 is a hydrogen atom may be converted into corresponding compounds having R4 other than the hydrogen atom in accordance with the reaction formula (17) below: 
wherein X5 represents a halogen atom such as chlorine, bromine and iodine or sulfonyloxy group such as toluenesulfonyloxy and mesyloxy, and the other symbols have the same meanings as defined hereinbefore.
The reaction of the formula (17) may be carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine and alcohol in the presence of a base in an amount of 1 to 2 times of the starting compound at a suitable temperature from room temperature to the boiling point of the solvent. Examples of the base include sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate, sodium hydride and the like.
The compounds of the invention where R5 is a hydroxy group, which are obtained in any of the reactions of formula (1) to (17), may be converted into corresponding compounds having a substituted hydroxyl group in accordance with any of the reaction formulae (18) to (21) below: 
wherein R14 represents an optionally branched alkyl group, optionally substituted aryl grow or heterocyclic group, X6 represents a halogen atom such as chlorine, bromine and iodine or xe2x80x94OCOR14, and the other symbols have the same meanings as defined hereinbefore.
The reaction of the formula (18) may be carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane and chloroform in the presence of a base in an amount of 1 to 2 times of the starting compound at a suitable temperature from room temperature to the boiling point of the solvent. Examples of the base include triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydroxide and the like. 
wherein R15 represents an optionally branched alkyl group or aralkyl group, X7 represents a halogen atom such as chlorine, bromine and iodine or xe2x80x94OCOOR15, and the other symbols have the same meanings as defined hereinbefore.
The reaction of the formula (19) may be carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane and chloroform in the presence of a base in as amount of 1 to 2 times of the starting compound at a suitable temperature from room temperature to the boiling paint of the solvent. Examples of the base include triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydroxide and the 
wherein R16 represents an optionally branched alkyl group or aralkyl group, X8 represents a halogen atom such as chlorine, bromine and iodine or sulfonyloxy group such as toluenesulfonyloxy and mesyloxy, and the other symbols have the same meanings as defined hereinbefore.
The reaction of the formula (20) may be carried out in a suitable solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane and chloroform in the presence of a base in an amount of 1 to 2 times of the starting compound at a suitable temperature from room temperature to the boiling point of the solvent. Examples of the base include triethylamine, pyridine, imidazole, sodium carbonate, potassium carbonate, sodium hydroxide and the like. 
wherein R17 represents an optionally branched alkyl group or aryl group, X9 represents an oxygen or sulfur atom, and the other symbols have the same meanings as defined hereinbefore.
The reaction of formula (21) may be carried out in an appropriate solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, pyridine, dichloromethane and chloroform at an appropriate temperature of from room temperature to the boiling point of the solvent.
The compounds of the present invention obtained as described hereinbefore and represented by the formula I or Ixe2x80x2 may be separated and purified by any of the conventional methods for the separation and purification of nucleosides, for example, recrystallization, adsorption chromatography, ion exchange chromatography and the like.
The compound of the invention represented by the formula I or Ixe2x80x2 may be converted into a pharmaceutically acceptable salt thereof by a conventional method. Such salt may be, for example, an alkali metal salt such as sodium or potassium salt, alkaline earth salt such as magnesium salt, ammonium salt or alkylammonium salt such as methylammonium, dimethylammonium, trimethylammonium, tetramethylammonium salt or the like.
The compounds according to invention can be administered to human beings via any route, oral, rectal, parenteral or local for the prevention or treatment of the infection of viruses such as retrovirus. The administration dose of the compounds according to the invention may be determined according to age, physical condition, body weight and the like of a patient to be treated; however, a suitable daily does of the compounds is 1 to 100 mg/(body weight)kg, preferably 5 to 50 mg/(body weight)kg and it is administered in one to several times.
The compound of the invents is generally prepared in a pharmaceutical composition with a suitable carrier, excipient and other additives. Either a liquid carrier or solid carrier may be suitably used for the present antiviral agent.
Examples of the solid carrier are lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride and the like.
Examples of the liquid are glycerin, peanut oil, polyvinyl pyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water and the like.
The present antiviral agent may be made in various forms. For example, it may be in the form of a tablet, powder, granule, capsule; suppository, troche or the like when a solid carrier is used, and it may be also in the form of syrup, emulsion, soft gelatin capsule, cream, gel, paste, spray, injection solution, or the like when a liquid carrier is used.
The novel 6-substituted ayclopyrimidine nucleoside derivatives according to the sent invention have an effective antiviral activity against viruses such as retrovirus and have a relatively low toxicity against the host cell, hence the derivatives of the invention are extremely useful as an active ingredient of antiviral agent.